While lung cancer is typically associated with smoking, lung cancer in people who have never smoked is, independently, the seventh most common cancer worldwide. About half of all lung cancers carry hallmark mutations in one of three oncogenes, EGFR, ALK and KRAS, which all have targeted therapies available or under development. Importantly, many targetable mutations appear more commonly in never-smokers’ lung cancers. “We want to find more targets for those never-smokers who are ‘triple negative’ and have no targeted therapies available to them,” says Geoffrey Oxnard, MD (DFCI), who is leading a new trial with that objective.

A New Target, A Candidate Therapy

Recently, Pasi Janne MD, PhD (DFCI), discovered a new therapeutic target in a subset of never-smokers with lung cancer: a rearrangement in RET, an oncogene previously implicated in thyroid cancer. RET is one of the genetic mutations targeted by the multi-kinase inhibitor sunitinib, which is an approved targeted therapy in kidney cancer and some sarcomas and pancreatic cancers. In addition to targeting RET, sunitinib inhibits the oncogenes VEGFR, KIT, PDGFR and FLT-3.

Sunitinib was previously described as being active in a small subset of lung cancers, but large Phase III trials failed to show a survival benefit. However, the trials did not select participants based on sensitizing genetic mutations to sunitinib, and a benefit to subgroups with sensitizing mutations may go undetected in an unselected population.

A Rational Trial and Objectives

Oxnard has now launched a Phase II trial to test the effectiveness of sunitinib in a selected population of never-smoker lung cancer patients without EGRF, ALK, or KRAS alterations. “We believe this enriched population of participants with wild-type cancers may have hidden alterations that explains their cancer, and we want to see if those alterations include RET or one of the other genes targeted by sunitinib,” explains Oxnard.

The trial will first assess the effectiveness of sunitinib in a selected population of patients with wild-type cancers, or who have a diagnosed RET mutation. A 30 percent response will be considered evidence of activity.

Second, investigators will use targeted next-generation sequencing to determine whether RET or previously undescribed genetic alterations in VEGFR, KIT, PDGFR or FLT-3 may explain the responses in these participants.

Targeted Next-Gen Sequencing

The targeted next-generation sequencing will be undertaken in collaboration with Nikhil Wagle, MD, in the lab of Levi Garraway MD, PhD (DFCI), who has developed platforms for comprehensively characterizing the genome of clinical cancer samples. For this study, however, the hypothesis-driven sequencing analysis will focus on just the handful of candidate genes of interest that are targets of sunitinib, thus reducing cost and improving efficiency of clinically relevant discovery.

Study Design

The Phase II study is an open-label single-arm trial with comparison to historical data. It is enrolling advanced lung adenocarcinoma in never-smokers who are wild-type on standard genotyping. A subset of patients must have a RET alteration. All patients must either have tumor biopsy tissue available, or undergo a biopsy, for next-generation sequencing. Subjects will receive sunitinib as an oral, outpatient therapy on an intermittent dosing schedule (4 weeks on/2 weeks off) with a daily dose of 50 mg.

The investigators are focusing on never-smokers because they are more likely to have a targetable mutation that can be treated with inhibitors. “Smokers have more genetically altered, complicated cancer genomes that are harder to treat with targeted therapies,” explains Oxnard. “Cancer in never-smokers often starts with a single bad-luck genetic alteration that may have a fantastic, durable response to the right therapy.” Based on both laboratory studies and clinical evidence, he is hopeful that sunitinib may be that right therapy in a portion of patients.

Phase II Trial

Title: Sunitinib in Never-Smokers With Lung Adenocarcinoma

Principal Investigator: Geoffrey Oxnard, MD (DFCI)

NIH Trial Number: NCT01829217

DF/HCC Protocol Number: 13-086

More Information:

The trial is ongoing and recruiting patients. Find more information at ClinicalTrials.gov.

Research detailed in this article was funded in part by NIH grants, including CA065164 and CA090578.